Clinical Trials /

Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions

NCT03937791

Description:

Background: Human papillomavirus (HPV) can cause vulvar high-grade squamous intraepithelial lesions (HSIL). Sometimes, this can become cancer. Researchers want to see if T cell therapy can treat vulvar HSIL. In this therapy, a person s immune cells are genetically modified so they can attack the HPV. Objective: To test if a personalized immune treatment can cure vulvar HSIL. Eligibility: People ages 18 and older with vulvar HSIL that cannot be removed with surgery, or for which surgery has failed Design: Participants will be screened with: Medical history Physical exam HPV testing Venous assessment Chest x-ray Heart and pulmonary tests Participants will have a baseline visit. They may have a vulvar biopsy. Photographs will be taken of their lesions. Participants will have leukapheresis: Blood is removed from a needle in the arm and circulated through a machine that takes out the white blood cells. The other blood cells are returned through a needle in the other arm. The white blood cells will be used to grow treatment cells. Participants will receive the treatment through a tube inserted into an arm, neck, or chest vein. They will recover in the hospital for 1 to 2 days. They will have blood tests and take supportive medications. Participants may have one more treatment. Participants will have 5 follow-up visits in the first 3 months after treatment. They may have more visits if their disease is growing. Visits will include blood tests. They may include vulvar biopsies or leukapheresis. Participants will have an annual physical exam for 5 years after treatment that can be done at home or at the NIH. Then they will have an annual phone or email questionnaire for another 10 years....

Related Conditions:
  • Vulvar Squamous Intraepithelial Lesion
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions
  • Official Title: A Phase II Study of Immunotherapy With E7 T Cell Receptor T Cells for Vulvar High-Grade Squamous Intraepithelial Lesions

Clinical Trial IDs

  • ORG STUDY ID: 190091
  • SECONDARY ID: 19-C-0091
  • NCT ID: NCT03937791

Conditions

  • Squamous Lntraepithelial Lesions of Vulva
  • Neoplasms, Squamous Cell
  • Vulvar HSIL

Interventions

DrugSynonymsArms
E7 TCRArm 1

Purpose

Background: Human papillomavirus (HPV) can cause vulvar high-grade squamous intraepithelial lesions (HSIL). Sometimes, this can become cancer. Researchers want to see if T cell therapy can treat vulvar HSIL. In this therapy, a person s immune cells are genetically modified so they can attack the HPV. Objective: To test if a personalized immune treatment can cure vulvar HSIL. Eligibility: People ages 18 and older with vulvar HSIL that cannot be removed with surgery, or for which surgery has failed Design: Participants will be screened with: Medical history Physical exam HPV testing Venous assessment Chest x-ray Heart and pulmonary tests Participants will have a baseline visit. They may have a vulvar biopsy. Photographs will be taken of their lesions. Participants will have leukapheresis: Blood is removed from a needle in the arm and circulated through a machine that takes out the white blood cells. The other blood cells are returned through a needle in the other arm. The white blood cells will be used to grow treatment cells. Participants will receive the treatment through a tube inserted into an arm, neck, or chest vein. They will recover in the hospital for 1 to 2 days. They will have blood tests and take supportive medications. Participants may have one more treatment. Participants will have 5 follow-up visits in the first 3 months after treatment. They may have more visits if their disease is growing. Visits will include blood tests. They may include vulvar biopsies or leukapheresis. Participants will have an annual physical exam for 5 years after treatment that can be done at home or at the NIH. Then they will have an annual phone or email questionnaire for another 10 years....

Detailed Description

      Background:

        -  Vulvar high-grade squamous intraepithelial lesion (HSIL) is a premalignant epithelial
           lesion that is frequently multifocal and/or recurrent.

        -  The primary treatment is surgery, which may result in disfigurement and compromise of
           the urethra, anus, or clitoris. Recurrence after surgery is common and primarily treated
           with additional surgery.

        -  Vulvar HSIL is caused by chronic infection with the human papillomavirus (HPV) type 16
           infection. In this clinical trial the HPV-16 infection is targeted with a single
           infusion of autologous T cells that have been genetically engineered to express a HPV-16
           E7-specific T cell receptor (E7 TCR T cells).

      Objective:

      -Determine the complete response rate for E7 TCR T cells in the treatment of vulvar HSIL.

      Eligibility:

        -  Histologically confirmed diagnosis of HPV-16+ vulvar HSIL.

        -  Expression of the HLA-A2*02:01 allele.

        -  Measurable lesion(s) that are recurrent or cannot be resected with acceptable cosmetic
           or functional results.

        -  Age greater than or equal to 18 years old.

        -  Eastern Oncology Cooperative Group Performance Score of 0 or 1.

      Design:

        -  This is a phase II clinical trial

        -  Simon minimax two-stage design with initial enrollment of 12 patients and expansion to
           16 patients if one or more complete response(s) is/are observed in the initial patients.

        -  Subjects will receive 1x1011 E7 TCR T cells

        -  No conditioning regimen or aldesleukin will be given

        -  Re-enrollment will be allowed for a small number of subjects.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1Experimental1x1011 E7 TCR T cells will be administered intravenously over 20 to 30 minutes on day 0.
  • E7 TCR

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have vulvar HSIL as confirmed by pathology report from a CLIA-certified
             laboratory.

          -  Vulvar HSIL must be HPV-16+ by a PCR, RNA, or in situ hybridization test from a CLIA
             certified laboratory.

          -  Patients must have measurable lesion(s) as defined in one or more of the following
             criteria:

               -  Failure of surgery to control disease (i.e. positive margins after surgery or
                  recurrence of HSIL after surgery).

               -  Multifocal or extensive disease for which surgery would result in disfigurement
                  that is not be acceptable to the patient.

               -  Disease for which surgery would have a risk of functional impairment that is not
                  be acceptable to the patient (i.e. involve partial or complete excision of the
                  clitoris, anus, vagina, or urethra).

          -  Patients may have received any previous therapy, including surgical excision. Patients
             with recurrent disease must have histologically documented recurrence on new biopsy
             and a measurable lesion that meets the above criteria.

          -  Patients must have the HLA-A*02:01 allele

          -  Age greater than or equal to18 years.

          -  ECOG performance status of 0-1.

          -  Able to understand and sign the Informed Consent Document.

          -  Women of child-bearing potential must have a negative pregnancy test. Women of
             child-bearing potential are defined as all women who are not post-menopausal or who
             have not had a hysterectomy. Postmenopausal will be defined as women over the age of
             55 who have not had a menstrual period in at least 1 year.

          -  The effects of E7 TCR T Cells on the developing human fetus are unknown. For this
             reason, women of child-bearing potential must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while she is participating in this study, she should inform her treating
             physician immediately.

          -  Seronegative for HIV antibody. The experimental treatment being evaluated in this
             protocol depends on an intact immune system. Patients who are HIV seropositive can
             have decreased immune-competence and thus be less responsive to the experimental
             treatment.

          -  Seronegative for hepatitis B antigen and hepatitis C antibody. If hepatitis C antibody
             test is positive, then the patient must be tested for the presence of antigen by
             RT-PCR and be HCV RNA negative.

          -  Must be willing to participate in Gene Therapy Long Term Followup Protocol (15-C-
             0141), which will follow patients for up to 15 years per Food and Drug Administration
             (FDA) requirements.

          -  Patients must have normal organ and marrow function as defined below:

               -  leukocytes greater than or equal to 3,000/mcL

               -  absolute neutrophil count greater than or equal to 1,000/mcL

               -  platelets greater than or equal to 100,000/mcL

               -  hemoglobin greater than or equal to 9.0 g/dL

               -  total bilirubin within 1.5X normal institutional limits except in patients with
                  Gilbert s Syndrome who must have a total bilirubin < 3.0 mg/dL

               -  AST(SGOT)/ALT(SGPT) Serum ALT/AST < 3X ULN

               -  creatinine < 1.5X baseline, < 1.5X ULN OR

               -  creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients
                  with creatinine levels above institutional normal (by the Chronic Kidney Disease
                  Epidemiology Collaboration (CKD-EPI) equation)

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents

          -  Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with E7 TCR, breastfeeding should be discontinued
             if the mother is treated with E7 TCR. These potential risks may also apply to other
             agents used in this study.

          -  Uncontrolled intercurrent illness including, but not limited to, any ongoing or active
             infection (e.g. requiring anti-infective therapy), coagulation disorders,
             cardiovascular disorders, respiratory disorders, cancer, or psychiatric illness/social
             situations (within the last six months) that would limit compliance with study
             requirements.

          -  Any form of systemic immunodeficiency, including acquired deficiency such as HIV or
             primary immunodeficiency such as Severe Combined Immunodeficiency Disease. The
             experimental treatment being evaluated in this protocol depends on an intact immune
             system. Patients who have decreased immune competence maybe less responsive to the
             treatment.

          -  Concurrent systemic steroid therapy if greater than the equivalent of 5 mg prednisone
             PO daily. Patients previously on steroids must be off steroids for four weeks prior to
             treatment.

          -  Cardiac stress test and pulmonary function tests maybe required for patients with a
             clinical history of significat cardiopulmonary disease. Patients with active cardiac
             ischemia or severe chronic obstructive pulmonary disease are not eligible.

          -  Patients with any active invasive cancer are not eligible.

          -  Patients with vulvar HSIL that is not HPV-16+ or is associated with multiple types of
             high-risk HPV at the time of eligibility assessment are not eligible.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine the complete response rate for E7 TCR T cells in the treatment of patients with vulvar HSIL.
Time Frame:3 months
Safety Issue:
Description:The fraction of patients who experience a complete response.

Secondary Outcome Measures

Measure:Characterize the safety profile of E7 TCR T cells administered in a low intensity setting without conditioning or systemic aldesleukin.
Time Frame:30 days following the last dose of study therapy
Safety Issue:
Description:List of toxicities identified by quantity, type, and grade.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Human Papilloma Virus (HPV) Type 16
  • Retroviral Vector Supernatant
  • Leukapheresis
  • T Cell Receptor
  • Premalignant Epithelial Lesion

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